Role Reversal: T Cells Instruct Dendritic Cells

Dendritic cells are antigen-presenting cells that activate T cells. More recently, signaling from the T cell to the dendritic cell has been reported for the dendritic cell B7 receptor and the T cell negative regulatory protein CTLA-4 (see Logue and Sha). Orabona et al. extend these findings and show that interaction between the dendritic cell B7 receptor and the T cell costimulatory receptor CD28 also delivers a signal to the dendritic cell. A soluble form of CD28 [a fusion of CD28 and immunoglobulin (Ig) (CD28-Ig)] bound to splenic dendritic cells and the production of interleukin 6 (IL-6) and interferon γ (IFN-γ) were stimulated. IL-6 was produced in greater amounts than IFN-γ and the amount of IFN-γ was approximately half that produced in response to CTLA-4. Using cells deficient in B7-1 or B7-2, both B7 receptors were determined to be required for maximal response to CD28. Using reporter gene expression, CD28, and not CTLA-4, was found to stimulate p38-regulated gene expression (fos promoter), whereas nuclear factor-κB (NF-κB)-regulated gene expression was stimulated by both CD28 and CTLA-4. The balance between an immunosuppressive and immunostimulatory response of dendritic cells involves SOCS3 (suppressor of cytokine signaling 3), and CD28 stimulated the transcription of SOCS3, thereby allowing the immunostimulatory effects of IL-6 to dominate. In vivo, the immunostimulatory effects of CD28 were observed in mice injected with CD28-Ig-treated dendritic cells that were also exposed to various antigens. This effect required activation of the IL-6 receptor and was blocked if the dendritic cells were simultaneously exposed to an antibody against the IL-6 receptor along with CD28-Ig. Injection of dendritic cells exposed to CD28-Ig with the yeast Candida albicans (as a source of antigen) resulted in enhanced immunity against the yeast. Finally, administration of CD28-Ig to mice harboring P1.HTR tumor cells, which evade immune elimination, caused tumor regression. Thus, the T cell:dendritic cell interface is a bidirectional signaling complex and the B7 binding partners on the T cells triggers either immunosuppressive (CTLA-4) or immunostimulatory (CD28) responses in the dendritic cells as well as the T cells.